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Wang, T.; Carrier, M. Immune Checkpoint Inhibitors-Associated Thrombosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/42716 (accessed on 11 July 2025).
Wang T, Carrier M. Immune Checkpoint Inhibitors-Associated Thrombosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/42716. Accessed July 11, 2025.
Wang, Tzu-Fei, Marc Carrier. "Immune Checkpoint Inhibitors-Associated Thrombosis" Encyclopedia, https://encyclopedia.pub/entry/42716 (accessed July 11, 2025).
Wang, T., & Carrier, M. (2023, April 01). Immune Checkpoint Inhibitors-Associated Thrombosis. In Encyclopedia. https://encyclopedia.pub/entry/42716
Wang, Tzu-Fei and Marc Carrier. "Immune Checkpoint Inhibitors-Associated Thrombosis." Encyclopedia. Web. 01 April, 2023.
Immune Checkpoint Inhibitors-Associated Thrombosis
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This entry is adapted from the peer-reviewed paper 10.3390/curroncol30030230

Tumor cells evade immune destruction by activating immune checkpoint receptor proteins including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) found on T cells, and programmed death ligand 1 (PD-L1) found on tumor cells. A type of novel anticancer therapy termed “immune checkpoint inhibitors (ICIs)” involves monoclonal antibodies that specifically target these proteins and prevent immune escape from tumor cells. Immune checkpoint inhibitors (ICIs) target programmed cell death (PD) 1 receptor and its ligand PD-L1, and have become an integral part of treatment regimens in many cancers including lung cancer, renal cell carcinoma, melanoma, and more. Cancer is associated with a significantly increased risk of venous thromboembolism compared to non-cancer patients, and the risks increase further with anticancer therapies including ICIs. Cancer-associated thrombosis can lead to hospitalizations, delayed cancer treatment, and mortality.

immune checkpoint inhibitors thrombosis cell death

1. Introduction

Tumor cells evade immune destruction by activating immune checkpoint receptor proteins including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) found on T cells, and programmed death ligand 1 (PD-L1) found on tumor cells. A type of novel anticancer therapy termed “immune checkpoint inhibitors (ICIs)” involves monoclonal antibodies that specifically target these proteins and prevent immune escape from tumor cells. Since the approval of the first ICI (ipilimumab) in 2011, seven ICIs have been approved in Canada and the United States in approximately 20 different malignancies (Table 1), including ipilimumab (anti-CTLA-4), nivolumab, pembrolizumab, cemiplimab (anti-PD-1), and atezolizumab, durvalumab, avelumab (anti-PD-L1). As such, patients eligible for ICI treatment significantly increased from 1.5% in 2011 to 43.6% in 2018 [1]. Sustained responses and significant improvement in survival have been seen with these novel therapies, and they have become the mainstay of therapies in many cancers such as melanoma, lung cancer, renal cell carcinoma (RCC), and more [2].
Table 1. Summary of approved immune checkpoint inhibitors (and their indications).
Immune Checkpoint Inhibitors Target Approved Indication
Ipilimumab CTLA-4 Melanoma
NSCLC
RCC
Colorectal cancer
Malignant pleural mesothelioma
Pembrolizumab PD-1 Melanoma
NSCLC
Urothelial carcinoma
RCC
Bladder cancer
Esophageal/esophagogastric junction cancer
Colorectal cancer
Endometrial cancer
Cervical cancer
Breast cancer
Head and neck squamous cell carcinoma
Hodgkin lymphoma
Primary mediastinal B cell lymphoma
Nivolumab PD-1 Melanoma
NSCLC
RCC
Head and neck squamous cell carcinoma
Classical Hodgkin lymphoma
Hepatocellular carcinoma
Cemiplimab PD-1 NSCLC
Cutaneous squamous cell carcinoma
Cutaneous basal cell carcinoma
Cervical cancer
Atezolizumab PD-L1 NSCLC
Small cell lung cancer
Urothelial carcinoma
Avelumab PD-L1 Urothelial carcinoma
Merkel cell carcinoma
Durvalumab PD-L1 NSCLC
Urothelial carcinoma
Mostly approved for unresected or metastatic cancers, refer to individual monographs for detailed approval indications for each cancer. Abbreviations: NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma.
Although thrombosis was not raised as a major concern in initial randomized controlled trials (RCTs) leading to the approval of ICIs, reports of thromboembolic disease had emerged from post-marketing wide use of these agents. Cancer-associated thrombosis is a known phenomenon, and it is estimated that 20% of cancer patients will develop thrombosis during their cancer journey [3]. It can result in hospitalizations, delayed cancer treatment, significant morbidity, and mortality [4][5]. Patients often experience psychosocial and financial distresses from the diagnosis of thrombosis as well [6][7]. Therefore, the optimal prevention and treatment strategies for cancer-associated thrombosis are crucial in the care of cancer patients.

2. Mechanism of Thrombosis and Immunotherapy

While the exact mechanisms of ICI-associated thrombosis remain unclear, studies have made strides to understand them. Programmed cell death protein 1 is crucial in downregulating pro-atherogenic T cell responses, so PD-1 antibodies can exacerbate atherosclerotic inflammatory vascular lesions [8]. Studies have shown that ICIs are found to be associated with increased T cell activation and endothelial inflammation, leading to thrombosis formation and accelerated atherosclerosis [9][10]. Similar to other immune-related adverse events associated with ICIs such as colitis and pneumonitis, ICIs release the break on immunoregulatory pathways, lead to an increase in inflammation and related cytokines, activate blood and endothelial cells, as well as release of neutrophil extracellular traps (NETs), and eventually result in thrombosis [11].

3. Incidence of Thrombosis in Patients Receiving Immune Checkpoint Inhibitors

Initial RCTs investigating the efficacy of ICIs as anticancer treatment did not report thrombosis as a major adverse event of concern. An initial meta-analysis of these RCTs showed a modest rate of VTE at 2.7% (95% confidence interval [CI] 1.8–4.0) and an arterial thrombosis (ATE) rate of 1.1% (95% CI 0.5–2.1) [12]. Another meta-analysis of RCTs and prospective studies of ICI use in patients with melanoma and non-small cell lung cancer (NSCLC) also reported similar rates (VTE rates: 1.5% in melanoma and 1.9% in NSCLC) [13]. Most recently, an updated meta-analysis showed no significantly increased risk of VTE (odds ratio [OR] 0.99, 95% CI 0.82–1.19) in patients treated with ICIs compared to non-ICI regimens [14]. However, all of these meta-analyses suffered from the possibility of underreporting of thrombosis events in RCTs in the first place. Solinas et al. excluded 40% of the eligible RCTs from analysis as they did not specifically report rates of thrombosis [12]. In addition, in these studies, thrombosis events were reported as adverse events based on the Common Terminology Criteria for Adverse Events (CTCAE) criteria instead of planned outcomes, and adverse events were often only reported if they were over certain percentages. Significant underreporting of thrombosis events had been shown in previous oncology RCTs with focus on efficacy of cancer therapies compared to thromboprophylaxis trials, which requires close attention for data interpretation [15].
Since the approval and wide clinical use of various ICIs, occurrences of venous and/or arterial thromboses are increasingly reported. Table 2 summarized the results of 27 cohort studies reported to date, with the majority being retrospective cohorts from single centers. Most (80–100%) patients had metastatic cancer, with the most common cancers including NSCLC, melanoma, and RCC. All studies included a variety of different ICIs available in clinical care. The incidence of thrombosis differed widely among studies, due to diverse types of underlying malignancies, concurrent cancer therapies (such as chemotherapy), and variable follow-up durations. In general, the incidence of VTE was 5–8% at 6 months and 10–15% at 12 months (Table 2). Overall, the rates reported in these retrospective cohort studies were higher than those reported from RCTs (1–2% in meta-analyses) [12][13], but not considerably higher when considering the 6-month risks of VTE of 9–10% in ambulatory cancer patients with Khorana score of ≥ 2 receiving chemotherapy [16]. However, given the efficacy of ICIs, the exposure of ICIs can be prolonged, and the risks of thrombosis can continue to accumulate. Sheng et al. showed that the thrombosis rate did not plateau until approximately 30 months in patients with metastatic RCC and 36 months in those with metastatic urothelial cancer [17][18]. Therefore, as patients continue ICIs, the risks of thrombosis can continue to increase. This is worth noting as compared to chemotherapy, for which the highest risk of thrombosis is typically seen within the first 6 months.
Table 2. Summary of incidence rates of venous and arterial thrombosis from retrospective studies of cancer patients receiving immune checkpoint inhibitors (studies missing follow-up durations were not included).
Study Country N Type of Cancer Stage IV Follow-up [Median (IQR)] VTE
Incidence % (95% CI)		 ATE
Incidence % (95% CI)
Hegde et al. 2017 [19] Abstract USA 76 Lung N/A 10.8 mo 18.4 2.6
Ibrahimi et al. 2017 [20]
Abstract		 USA 154 Lung 20.8% Melanoma 20.1%
Ovarian 12.3%		 92% 7 mo (198 days) 10.4 0
Bar et al. 2019 [21] Israel 1215 All cancers
Melanoma 40.5% Lung 28.7%		 N/A 12 mo AVE (MI, stroke, PE, DVT)
6 mo: 4.9
12 mo: 5.8
Nichetti et al. 2019 [22] Italy 217 NSCLC 95.4% 37.8 mo 7.4 6.5
Ando et al. 2020 [23] Japan 122 Lung, kidney, stomach, urothelial, melanoma N/A N/A
Time to thrombosis 90 days (range 6–178)		 4.1 4.9
Drobni et al. 2020 [24] USA 2842 All cancers
NSCLC 28.8% Melanoma 27.9%		 N/A 2 years N/A Composite: 5.35/100 person-yrs
MI: 2.49
Stroke: 2.08
Deschênes-Simard et al. 2021 [25] Canada 593 NSCLC 87.2% 12.7 (4.9–22.7) mo 9.9 (7.5–12.3)
76.5 (59.9–97.8) per 1000 person-years		 1.3
Gong et al. 2021 [26] USA 2854 All cancers
NSCLC 28.4% Melanoma 28.2%		 N/A 194 days (IQR 65–412) 6 mo: 7.4
12 mo: 13.8		 N/A
Gutierrez-Sainz et al. 2021 [27] Spain 229 Lung 48%
Melanoma 23.6%
RCC 11.8%		 96.5% 9.8 mo 7 (4–10) N/A
Guven et al. 2021 [28] Turkey 133 RCC 26.3%
Melanoma 24.1% NSCLC 18.8%		 100% 10.1 (5.8–18.5) mo 11.3 N/A
Haist et al. 2021 [29] Germany 280 Melanoma 100% 28 mo (95% CI 23.4–32.6) 12.5 4.3
Hill et al. 2021 [30] USA 435
(a) ICI: 171
(b) ICI+chemo: 157
(c) chemo then durvalumab: 107		 NSCLC 47% N/A 6 mo:
(a) 7.6 (4.3–12.2)
(b) 9.9 (5.8–15.3)
(c) 9.4 (4.8–15.8)
12 mo:
(a) 9.0 (5.3–14.0)
(b) 12.8 (7.8–19.0)
(c) 12.2 (6.8–19.2)		 N/A
Icht et al. 2021 [31] Israel 176 NSCLC 85.8% 6 mo (187 days) 4.5 (2.1–8.3) N/A
Kewan et al. 2021 [32] USA 552 All cancers
NSCLC 47.3%		 100% 12.1 mo 12.1 1.3
Madison et al. 2021 [33] ^ USA 6127 Lung N/A 6 mo 6.3 2.6
Moik et al. 2021 [34] Austria 672 Melanoma 30.4%
NSCLC 24.1%
RCC 11%		 85.8% 8.5 mo 6 mo: 5.0 (3.4–6.9)
12mo: 7.0 (5.1–9.3)
Overall: 12.9 (8.2–18.5)		 6 mo: 1.0 (0.4–2.0)
12 mo: 1.8 (0.7–3.6)
Overall 1.8 (0.7–3.6)
Roopkumar et al. 2021 USA 1686 Lung 49.6% Melanoma 13.2% 90.3% 438 days (range 7–1971) 6 mo: 7.1
12 mo: 10.9
Overall: 24		 N/A
Sheng et al. 2021 [17] USA 351 RCC 100% 12.8 mo 11 2
Total thromboembolism:
6 mo: 4.4 (2.6–6.9)
12 mo: 9.8 (6.8–13.4)
Sussman et al. 2021 USA 228 Melanoma 81.1% 27.3 mo 6 mo: 8.0 (4.9–12.0)
12 mo: 12.9 (8.9–17.7)		 6 mo: 2.2 (0.8–4.8)
12 mo: 4.5 (2.3–7.8)
Alma et al. 2022 [35] France 481 Lung 86% 9.8 mo 9.8 N/A
Bjornhart et al. 2022 [36] Denmark 146 prospective (A) * NSCLC 87% 16.5 mo 6 mo: 13.0
12 mo: 14.4
Overall: 14		 N/A
426 retrospective (B) 6 mo: 4.9
12 mo: 5.6
Overall: 6
Canovas et al. 2022 [37] Spain 665 Lung 91.2% 14 mo 6.9 1.5
All thrombosis: 8.4 (6.23–10.6)
291 Melanoma 82.5% 17 mo 4.8 1.0
All thrombosis: 5.8 (3.34–9.18)
Endo et al. 2022 [38] Japan 120 Lung 62.5% within 6 mo 2.5 4.2
Khorana et al. 2023 [39] ^ USA (a) ICI: 605
(b) ICI+chemo: 602		 NSCLC 100% 9.1 mo 6 mo:
(a) 8.1
(b) 12.8
12 mo:
(a) 13.5 (10.6–16.5)
(b) 22.4 (20.2–24.5)		 N/A
May et al. 2022 abstract [40] ^ USA 1823 All cancers N/A 6 mo 7.3 N/A
Sanfilippo et al. 2022 abstract [41]^ USA 1754 All cancers 77.9% 6 mo 4.1 N/A
Sheng et al. 2022 [18] USA 279 Urothelial 100% 5.6 mo 13 2
Total thromboembolism:
6 mo: 9.1 (6.0–13.0)
12 mo: 13.6 (9.6–18.4)
* A prospective cohort employed screening-detected VTE by computed tomography venography and pulmonary angiography. ^ Outcomes identified by ICD codes. Gong: VTE after ICI compared to pre, HR 4.98 (3.65–8.59). Abbreviations: ATE—arterial thrombosis; AVE—arterial event; CI—confidence interval; DVT—deep vein thrombosis; ICI—immune checkpoint inhibitor; MI—myocardial infarction; mo—months; N/A—not available; NSCLC—non-small cell lung cancer; PE—pulmonary embolism; RCC—renal cell carcinoma; USA—United States of America; VTE—venous thromboembolism.
In addition to retrospective cohort studies, three Danish population cohort studies reported the incidence of thrombosis in patients on ICIs (Table 3) [42][43][44]. It is interesting to note that the rates of thrombosis appear to be numerically lower in the population studies compared to the above-mentioned retrospective studies, with 6-month VTE rate of 2–4% and 4–7% at 12 months. In these population studies, outcomes were identified by ICD10 codes +/− imaging codes (as compared to individual chart review in retrospective studies), which could account for the difference in event rates. In addition, all three studies were from a single country (Danish registry), as compared to various countries from cohort studies (Table 2).
Table 3. Summary of incidence of VTE and ATE from population cohort studies (all from Danish registries).
Study N Type of cancer Follow-up (mo) VTE (%), (95% CI) ATE (%), (95% CI)
Mulder et al. 2021 [43] 370 All cancers 6 4.1 (2.3–6.7) N/A
12 7.1 (4.2–11.1)
Moik et al. 2021 [43] Abstract 3259 All cancers 6 3.9 (3.3–4.7) 1.3 (0.9–1.8)
12 5.7 (4.9–6.6) 2.2 (1.7–2.8)
24 7.3 (6.2–8.4) 3.1 (2.4–3.8)
Overvad et al. 2022 [44] 3946 All cancers 6 2.6 1.3
12 3.8 1.9
Abbreviations: ATE—arterial thrombosis; CI—confidence interval; mo—months; VTE—venous thromboembolism.
Whether ICI combinations or combined ICI and chemotherapy would be associated with an increased risk of VTE (compared to single ICI or chemotherapy alone) is also an area of debate. Sussman et al. showed that ICI combinations were associated with a higher risk of VTE compared to single agent ICI [45]. A recent meta-analysis also showed that compared to mono-ICI, combined ICIs were associated with an increased risk of VTE and myocardial infarction in those with NSCLC [13]. However, another study showed that combined ICIs were not associated with higher risks [46]. Similarly, some studies showed an increased risk of ICI–chemotherapy combination compared to chemotherapy alone [30][41], while others showed similar rates of thrombosis in patients receiving ICI alone, chemotherapy alone, or combination [21]. Most recently, in the analysis of an oncology database of 2299 patients with stage IV NSCLC, first-line ICI-based regimens were associated with a 26% reduction in the risk of VTE compared to chemotherapy-based regimens, while the risks were comparable between ICI/chemo versus chemotherapy alone [39]. It is worth noting that a fair comparison of the risks of thrombosis associated with combination of chemotherapy and ICIs to ICI alone or chemotherapy alone could be challenging, as the baseline characteristics of these patients commonly differ significantly.
Data on the incidence or arterial thrombosis were even more scant, with rates within 1-2% over a follow-up period of 6 to 17 months (Table 2). A recent meta-analysis showed an increased risk of arterial thrombosis (OR 1.58, 95% CI 1.21–2.06) associated with ICI regimens [14]. In a matched cohort study of 2842 patients, Drobni et al. revealed that there was a three-fold increased risk of cardiovascular events after the start of ICIs compared to other anticancer therapies. The risks were similarly increased when they compared before and after ICI use in the same patients [24]. They also found ICI to be associated with a > three-fold higher rate of progression of total aortic plaque volume, which can be attenuated with concomitant use of corticosteroids or statins [24].

4. Prevention and Treatment of Thrombosis in Patients on Immune Checkpoint Inhibitors

Recent RCTs including AVERT and CASSINI trials demonstrated the efficacy and safety of prophylactic doses of apixaban and rivaroxaban, respectively, in the prevention of cancer-associated thrombosis in ambulatory cancer patients with intermediate-high risk patients (Khorana score ≥ 2) [47][48]. Major international guidelines have since suggested consideration of primary VTE prophylaxis in this population [49][50]. However, whether this practice can also apply to patients receiving ICIs remains unclear, as Khorana score, derived from a chemotherapy-treated population, had been shown to be suboptimal in risk stratification for patients on ICIs [17][22][28][30][31][32][34][35][36]. Patients with Khorana score of ≥ 2 on chemotherapy are associated with a 6-month risk of VTE of 9–10% [16], and whether the ICI-treated population with a 6-month VTE risk of 5–8% can derive sufficient benefit to warrant primary thromboprophylaxis in all patients receiving ICIs remains investigational. Further identification of high-risk patient population may be needed.

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Tzu-Fei Wang
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